Research in mice reveals that certain immune cells might be implicated in blood pressure control. Initial observations conducted in patients corroborate the existence of such a mechanism. If this finding is confirmed, it could pave the way for new therapeutic approaches in hypertension, particularly in patients with inflammatory vascular diseases.

Pierre-Louis Tharaux

Pierre-Louis Tharaux. Courtesy: Inserm.fr

Characterized by an abnormally high pressure of the blood on the blood vessel walls, the origin of hypertension (HT) is multifactorial: aging, excess weight, sedentary lifestyle, smoking, diet and many other factors are implicated in its development, not all of which have been identified. Over previous years, an increasing amount of data is pointing to the specific role of immunity in the development of the condition.

Researchers from Inserm, in collaboration with a team in Scotland, have recently confirmed this by describing the key role of the macrophages: these immune cells are thought to control levels of endothelin-1 (ET-1), a peptide produced by the human body which promotes blood vessel contraction and as such raises blood pressure. If confirmed, these findings could pave the way for new antihypertensive treatments targeting this mechanism.

Macrophage regulation

The researchers focused their attention on the macrophages. “These immune cells normally participate in recognizing and then eliminating elements present in the tissues – degradation products, infectious agents, and more,” explains Pierre-Louis Tharaux, who is leading the team behind this research. “We observed that they present two types of ET-1 receptors on their surface: ETA and ETB.

By studying the functioning of these receptors, the researchers noted that the macrophages were drawn to ET-1, which was mediated by the ETB receptors. Another new finding is that the occupation of the ETB receptors by ET-1 causes the disappearance of the ET-1 in human or mouse macrophage cultures. “We wanted to understand the mechanism involved: tests on human cell cultures have shown that the macrophages capture ET-1 in order to degrade it by internalizing it using an endocytosis mechanism dependent on the ETB receptor.” This new function of ET-1 “purification” by the macrophages was observed in vivo, in mouse models of hypertension. “When we genetically deleted the macrophages in the mice, we observed that the animals presented an increased susceptibility to HT. Likewise, the selective inactivation of the ETB receptor on the surface of the macrophages was enough to increase blood levels of ET-1 and render the mice much more sensitive to various HT induction models.

The macrophages would therefore have a role in regulating the levels of ET-1 produced by the cells of the vascular endothelium. They are thought to modulate the constriction response, and as such blood pressure.

Hypertension – from management to consequences

In parallel, a team of colleagues at the University of Edinburgh studied cases of patients with inflammatory diseases of the small vessels, with accelerated cardiovascular and renal aging. These patients presented high blood levels of ET-1 and were frequently hypertensive. These were patients treated with immunosuppressants, some of which reduce the quantity of macrophages and their precursors (monocytes) and others not. The doctors were surprised to observe that the increase in ET-1 and in blood pressure was observed only in patients whose treatment reduced the number of monocytes in the blood, as predicted by the mouse models.

These findings could therefore lead to therapeutic changes: they could encourage practitioners to choose immunosuppressants according to their more or less strong capacity to suppress monocyte or macrophage levels, or to combine them with antihypertensive treatments which do not have an effect on the ETB receptors or which block the ETA vascular receptor, whose stimulation also contracts the arteries. A particularly important prospect in public health terms, given that half of the more than 7.6 million hypertensives in France do not have their blood pressure under control.

Tharaux’s team would now like to know more about the interaction between immunity and the organ lesions observed in the severe forms of HT. “We have observed that ET-1, which is produced by the vascular endothelium but also by other tissues systematically causes macrophage recruitment. Yet poorly controlled HT gradually promotes microvascular lesions in some particularly vulnerable organs (kidneys, brain, retina, heart). We will therefore try to understand how and to what extent the macrophages are involved in this mechanism.

*Unit 970 Inserm/Université Paris Descartes, Paris Cardiovascular Research Center

Reference:

Czopek A et coll. A novel role for myeloid endothelin-B receptors in hypertension. European Heart Journal doi: 10.1093/eurheartj/ehy881

Source: https://www.inserm.fr/en/